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Rosiglitazone restores renal D_1A receptor-G_s protein coupling by reducing receptor hyperphosphorylation in obese rats

Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas

Submitted 27 September 2004 ; accepted in final form 22 March 2005

Dopamine D_1A receptor function is impaired in obesity-induced insulin resistance, contributing to sodium retention. We showed previously that uncoupling of D_1A receptors from G proteins is responsible for diminished natriuretic response to dopamine in obese Zucker rats (OZRs). We hypothesized that overexpression of G protein-coupled receptor kinases (GRKs) leads to increased phosphorylation of D_1A receptors, which in turn causes uncoupling of the receptors from G_s proteins in proximal tubules of OZRs. We also examined effects of an insulin sensitizer, rosiglitazone, in correcting these defects. We found that basal and agonist (fenoldopam)-induced coupling of D_1A receptors to G_s proteins was impaired in proximal tubules of OZRs compared with lean Zucker rats (LZRs). Moreover, basal serine phosphorylation of D_1A receptors was elevated two- to threefold in proximal tubules of OZRs compared with LZRs. Fenoldopam increased D_1A receptor phosphorylation in proximal tubules of LZRs but not OZRs. Compared with that in LZRs, GRK4 expression in OZRs was elevated 200–300% in proximal tubule cell lysates and GRK2 expression was 30% higher in plasma membranes isolated from proximal tubules of OZRs. Rosiglitazone treatment restored basal and agonist-induced coupling of D_1A receptors to G_s proteins and reduced basal serine phosphorylation of D_1A receptors, GRK4 expression, and translocation of GRK2 to the plasma membrane in proximal tubules of OZRs. Furthermore, rosiglitazone significantly reduced fasting blood glucose and plasma insulin in OZRs. Collectively, these results suggest that insulin resistance is responsible for GRK4 overexpression and GRK2 translocation leading to hyperphosphorylation of D_1A receptors and their uncoupling from G_s proteins as rosiglitazone treatment corrects these defects in OZRs.

dopamine; D_1A receptors; hyperphosphorylation; G protein-coupled receptors; kidney; obesity

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